US20070140915A1 - Method and Apparatus for Obtaining Aliquot from Liquid-Based Cytological Sample - Google Patents

Abstract

An instrument for automated processing of sample vials are provided. The instrument causes an aliquot chamber within the vial to be filled with the fluid contained within the vial.

Description

RELATED APPLICATIONS
• The present application is a continuation-in-part of the U.S. application Ser. No. 11/299,394, filed on Dec. 12, 2005 by Watts et al. and entitled “METHOD AND APPARATUS FOR OBTAINING ALIQUOT FROM LIQUID-BASED CYTOLOGICAL SAMPLE”, the entire disclosure of which is hereby incorporated by reference herein, including all the drawings.
FIELD OF THE INVENTION
• The present invention pertains to the preparation of cytological samples, and more specifically, to a method and apparatus for obtaining aliquots from cytological samples, such as fluid-based Papanicolaou (“Pap”) smears.
BACKGROUND
• When a -based Pap smear is performed, the specimen will be classified as either normal or abnormal based on the microscopic analysis of the slide. An abnormal sample can be classified into one of the major categories defined by The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnostics, which categories include Low-Grade Squamous Intraepithelial Lesions (LSIL), High-Grade Squamous Intraepithelial Lesions (HSIL), Squamous Cell Carcinoma, Adenocarcinoma, Atypical Glandular cells of Undetermined Significance (AGUS), Adenocarcinoma in situ (AIS), and Atypical Squamous Cell (ASC), which can be further sub-divided into Atypical Squamous Cell, cannot exclude HSIL (ASC-H) and Atypical Squamous Cell of Undetermined Significance (ASC-US).
• Since 2000, a specific Human Papilloma Virus (HPV) deoxynucleic acid (DNA) test, referred to as the Hybrid Capture II HPV DNA assay, manufactured by Digene Corporation, has been used to determine whether patients, whose Pap smears have been classified as ASC-US, have HPV. Based on the strong correlation between HPV and cervical cancer, it has been recommended that HPV DNA testing be used as a triage test for patients whose Pap smear results are classified as ASC-US.
• In the case where a liquid-based Pap smear has been performed the same sample used to perform the Pap smear analysis can be conveniently used to perform a “reflexive” HPV DNA test, thereby obviating the need for a repeat clinic visit and Pap smear. In this case, if a slide is positive for ASC-US, an aliquot (e.g., 4 mL) of the fluid sample is removed from the stored vial and sent to a molecular diagnostic laboratory for HPV DNA testing.
• Significantly, laboratories that perform HPV DNA tests are weary of molecular contamination—a well-known problem in molecular diagnostic laboratories. Thus, due to the risk of cross-contamination, molecular diagnostic laboratories may not accept aliquots that have been taken from an already processed liquid-based Pap smear for fear of unnecessarily generating false HPV positives.
SUMMARY OF THE INVENTION
• In accordance with an aspect of the invention, an instrument is provided, which comprises a mechanical arm and an actuator. The mechanical arm is configured to obtain a vial from an input location and transport it to the actuator. The actuator is configured to unseal the aliquot chamber, fill the aliquot chamber with a portion of a fluid contained within the collection chamber of a vial, and then seal the aliquot chamber. The mechanical arm then transports the vial to an output location.
• Other and further aspects and features of the invention will be evident from reading the following detailed description of the preferred embodiments, which are intended to illustrate, not limit, the inventions.
BRIEF DESCRIPTION OF THE DRAWINGS
• The drawings illustrate the design and utility of preferred embodiments of the present invention, in which similar elements are referred to by common reference numerals. In order to better appreciate how the above-recited and other advantages and objects of the present inventions are obtained, a more particular description of the present inventions briefly described above will be rendered by reference to specific embodiments thereof, which are illustrated in the accompanying drawings. Understanding that these drawings depict only typical embodiments of the invention and are not therefore to be considered limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:
• FIG. 1 is a perspective view of one embodiment of a sample vial constructed in accordance with the present invention;
• FIG. 2 is a cross-sectional exploded view of the sample vial ofFIG. 1, particularly showing a valve mechanism in an open position;
• FIG. 3 is a cross-sectional exploded view of the sample vial ofFIG. 1, particularly showing the valve mechanism is the closed position;
• FIG. 4 is a close-up cross-sectional view of a vial cap of the sample vial ofFIG. 2;
• FIG. 5 is a close-up cross-sectional view of an alternate vial cap that can be used with the sample vial ofFIG. 1, particularly showing a valve mechanism in an open position;
• FIG. 6 is a close-up cross-sectional view of vial cap ofFIG. 5, particularly showing the valve mechanism in a closed position;
• FIG. 7 is a close-up cross-sectional view of another alternative vial cap that can be used with the sample vial ofFIG. 1, particularly showing a valve mechanism in an open position;
• FIG. 8 is a close-up cross-sectional view of vial cap ofFIG. 7, particularly showing the valve mechanism in a closed position;
• FIG. 9 is a cross-sectional exploded view of another embodiment of a sample vial constructed in accordance with the present inventions, particularly showing a valve mechanism in an open position;
• FIG. 10 is a cross-sectional exploded view of the sample vial ofFIG. 9, particularly showing the valve mechanism is the closed position;
• FIG. 11 is a close-up cross-sectional view of a vial cap of the sample vial ofFIG. 10; and
• FIG. 12 is a flow diagram of a method for processing the foregoing sample vials.
DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
• Referring toFIG. 1, asample vial10 constructed in accordance with one embodiment of the present invention will be described. Thevial10 may be used to contain a fluid-based sample, such as a cervical-vaginal sample collected from a patient at a physician's office. The fluid-based sample typically comprises cytological material suspended in an aqueous preservative fluid.
• To this end, thevial10 comprises ahollow vial container12 and avial cap14 that can be placed onto thevial container12 to enclose a sample contained within thevial container12. As depicted, thevial container12 andvial cap14 are generally cylindrical in shape. The selected size of thevial container12 andvial cap14 may vary, but preferably is large enough to contain the minimum amount of sample necessary to perform the intended diagnostic test. In the illustrated embodiment, thevial container12 is capable of containing at least 20 mL of fluid, which is the minimum amount of sample required by the Food and Drug Administration (FDA) for automated transfer onto a microscope slide using Cytye's ThinPrep® 2000 or Thinprep® 3000 slide preparation systems. For example, thevial container12 may have an outer diameter of approximately 1 and 5/16 inches and an axial length of approximately 2 and ¾ inches, and thevial cap14 may have an outer diameter of approximately 1 and 9/16 inches and an axial length approximately 7/16 of an inch.
• Thevial container12 is composed of a translucent or transparent material to allow a user to determine the fluid level inside of thevial10. A suitable material is a plastic, such as polypropylene homopolymer, available under the trade designation AMOCO 4018. Thevial cap14 may be releasably mated with thevial container12 using a standard threaded engagement (not shown), and may be composed of a plastic material, such as polypropylene random copolymer, available under the trade designation AMOCO 8949. The materials of which thevial container12 andvial cap14 are composed may be injection molded to rapidly and inexpensively produced thecontainer12 andcap14, although other suitable manufacturing processes may be utilized depending on the particular materials selected.
• A seal (not shown) may be disposed between thevial container12 andcap14 to form a fluid-tight seal when sufficient torque is applied to thecap14 relative to thecontainer12. Sealing is important to prevent both leakage and evaporation of the preservative solution in thevial container12, as well as to prevent the sample from being exposed to external contaminants. The seal may be composed of any material or materials capable of withstanding attack by the preservation solution in thevial container12, which typically includes an alcohol solution, such as methanol in a buffer. Due to the low viscosity and high vapor pressure of the preservative solution, as well as the very low density and high permeability of the vapor phase thereof, a high integrity, reliable, seal composition is desired. Further, because thevial10 may be stored for a year or more prior to use, and be subject to temperature extremes during transport and storage, the seal should be capable of retaining its sealing characteristics and structural integrity for extended periods of time without excessive loss of fluid due to evaporation. The seal material also should not degrade and contaminate the sample. In one embodiment that meets these requirements, the seal is composed of a multicomposite material, including a sufficiently thick, dense, resilient layer disposed on a vapor barrier. The resilient layer may be oriented toward the sample to provide an effective seal. The seal may include a synthetic olefin rubber or an elastomeric alloy co-extruded on a thin vapor barrier, such as that available from Tri-Seal, Inc., located in Blauvelt, N.Y., and sold under the trade name TRI SEAL SOR-117.
• Thevial container12 includes afluid level indicia16 by which a user may determine a proper amount of preservation fluid to fill thevial10 or that thevial10 is filled properly prior to addition of the cytological material. Thefluid level indicia16 may be a frosted annular band of a predetermined axial length disposed about a circumference of thevial container12 at a predetermined axial location to indicate the acceptable fill range of thevial10, so that a proper slide sample can be prepared from the sample by an automated specimen preparation system, such as Cytyc's ThinPrep® 2000 or ThinPrep® 3000 slide preparation systems. Alternatively, thefluid level indicia16 may be a single fill line or an upper fill line and a lower fill line, in which case, the upper fill line indicates a maximum level to which thevial container12 should be filled and the lower fill line indicates a minimum amount of fluid necessary to prepare a specimen from the sample.
• Thevial container12 also includessample indicia18, which can be used to identify a patient to whom the sample corresponds, as well as a slide prepared from the sample contained in thesample vial10. Thesample indicia18 may be machine-readable, such as a bar code, which can be ready by an automated cytological specimen preparation system, such as Cytyc's ThinPrep® 2000 or ThinPrep® 3000 slide preparation system.
• In an optional embodiment, thevial container12 andvial cap14 may be specially configured for automated manipulation. For example, thevial container12 may have laterally protruding anti-rotation lugs (not shown), and thevial cap14 may have a torque pattern of ribs (not shown), thereby allowing thecap14 to be screwed on and screwed off of thevial container12 using automated machinery. Additional details regarding these features are disclosed in U.S. patent application Ser. No. 09/156,952, entitled “Sample Vial for Use in Preparing Cytological Specimen,” which is fully and expressly incorporated herein by reference.
• Referring further toFIGS. 2 and 3, thevial10 includes a feature that allows an aliquot sample to be taken and isolated from the sample contained within thevial container12. In particular, thevial10 comprises acollection chamber20 formed within thevial container12 for collection of the sample, analiquot chamber22 for containing the aliquot sample, and avalve mechanism24 for selectively sealing and unsealing thealiquot chamber22 from thecollection chamber20, so the aliquot sample can be transferred from thecollection chamber20 into thealiquot chamber22 where it can be isolated from the remaining portion of the sample within thecollection chamber20. In the illustrated embodiment, thealiquot chamber22 abuts thecollection chamber20, although alternatively,aliquot chamber22 may communicate with thecollection chamber20 via, e.g., a passageway.
• In the embodiment illustrated inFIGS. 2 and 3, thealiquot chamber22 andvalve mechanism24 are carried by thevial cap14. In particular, thevial cap14 includes an outerannular flange26, an innerannular flange28, and anannular space30 between theflanges26,28. Thevial container12 includes alip32 that is sized to fit within theannular space30 of thevial cap14 in a snug manner, so that theinner surface34 of the outerannular flange26 bears against theouter surface36 of thevial container12, and theouter surface38 of the innerannular flange28 bears against theinner surface40 of thevial container12, as best illustrated inFIG. 4. In the illustrated embodiment, theinner surface34 of the outerannular flange26 and theouter surface36 of thevial container12 include threads (not shown), so that thevial cap14 can be firmly screwed on thevial container12. As can be seen, the innerannular flange28 of thevial cap14 defines thealiquot chamber22 therein, which absent thevalve mechanism24, would normally be in fluid communication with thecollection chamber20 when thevial cap14 is mated with thevial container12.
• Thevalve mechanism24 includes avalve42 that is configured to directly interface with thealiquot chamber22 to allow or prevent fluid communication with thecollection chamber20. In the embodiment illustrated inFIGS. 2 and 3, thevalve42 is configured to be selectively displaced from the aliquot chamber to allow fluid communication between thealiquot chamber22 and the collection chamber20 (FIG. 2), and located within thealiquot chamber22 to prevent fluid communication between thealiquot chamber22 and the collection chamber20 (FIG. 3).
• As best shown inFIG. 4, when preventing fluid communication between therespective chambers20,22, thevalve42 sealingly bears against theinner surface44 of the innerannular flange28. To this end, thevalve42 includes anannular flange46 that has a diameter slightly smaller than the diameter of thealiquot chamber22 and an O-ring seal48 seated within anannular recess50 formed around the circumferential edge of theannular flange46, so that the total diameter of thevalve42 is slightly greater than the diameter of thealiquot chamber22 in order to facilitate the sealing arrangement.
• Thevalve mechanism24 further includes anactuator52, which includes ashaft54 coupled to thevalve42 and aboss56 coupled to the end of theshaft54 and extending up through anupper bore58 formed in thevial cap14. As such, theboss56 can be externally manipulated to selectively displace thevalve42 from thealiquot chamber22 by axially moving theactuator shaft54 downward, and locate thevalve42 within thealiquot chamber22 by axially moving theactuator shaft54 upward. Theannular flange46 of thevalve42, theshaft54, and theboss56 may be conveniently formed from the same material as a unibody design, e.g., in an injection molding process using a plastic material, such as polypropylene or Acrylonitrile Butadiene Styrene (ABS).
• As best shown inFIG. 4, in order to prevent fluid communication between thealiquot chamber22 and the external environment that may otherwise occur through theupper bore58, thevalve mechanism24 includes an O-ring seal60 seated within anannular recess62 formed around the circumference of theshaft54. The O-ring seal60 axially moves within an enlargedlower bore64 between theupper bore58 and thealiquot chamber22. In the illustrated embodiment, thelower bore64 is defined by an innermostannular flange66 formed within thevial cap14, so that the O-ring seal60 bears against aninner surface68 of the innermostannular flange66. Thus, the O-ring seal60 axially moves within thelower bore64 in a sealing arrangement to allow theactuator shaft54, and thus, thevalve42, to move up or down relative to aliquotchamber22, while preventing fluid communication between thealiquot chamber22 and the external environment through theupper bore58.
• In the embodiment illustrated inFIGS. 2 and 3, axial movement of theactuator shaft54 is accomplished by rotationally translating the boss56 (shown by arrow), and thus, theshaft54, to operably move thevalve42 relative to thealiquot chamber22. To this end, as best shown inFIG. 4, a threadedarrangement70 is provided between theactuator shaft54 and theupper bore58. Thus, clockwise rotation of theboss56 causes theshaft54, and thus thevalve42, to move axially downward, and counterclockwise rotation of theboss56 causes theshaft54, and thus thevalve42, to move axially upward. As can be appreciated, theboss56, which is larger than theshaft54, allows the user to more easily and ergonomically rotate theshaft54 against any frictional resistance caused by the interaction of thevalve42 andaliquot chamber22. Theboss56 can be further provided with a knurled surface (not shown) to facilitate gripping by the user. Alternatively, rather than using a boss or any other element that protrudes from the top of thevial cap14, a slot or other suitable pattern can be formed at the end of theshaft54 to allow a tool, such as a screw driver, to be mated with theshaft54 for subsequent rotation thereof.
• To allow user access to the aliquot sample, thevial cap14 includesaccess port72 adjacent thealiquot chamber22 and a sealing mechanism in the form ofseptum74 seated within theaccess port72 to seal it, thereby preventing fluid communication from thealiquot chamber22 through theaccess port72 until the user is ready to remove the aliquot sample from thealiquot chamber22 for examination. User access to the aliquot sample can be accomplished, e.g., by puncturing theseptum74 with a syringe (not shown) and drawing the aliquot sample from thechamber22 into the syringe. Alternatively, a seal may be bonded on top surface of thevial cap14 above theaccess port72 or a screw-on plug or cap can be used to seal theaccess port72.
• Referring now toFIGS. 5 and 6, an alternative embodiment of avial cap84 will be described. Thevial cap84 is identical to thevial cap14 illustrated inFIGS. 2 and 3, which the exception that it comprises avalve mechanism86, wherein theactuator shaft54 is configured to be only axially translated, i.e., without rotational translation. In this case, there is no threaded arrangement between theshaft54 and theupper bore58. Rather, theactuator shaft54 is slidably engaged with thebore58 in the axial direction, so that a user may simply push or pull theshaft54 to axially move thevalve42 relative to thealiquot chamber22. Thevalve mechanism86 comprises aspring88 disposed between anannular flange90 inwardly extending from the innermostannular flange66 at the bottom of the enlargedlower bore64 and anannular flange92 outwardly extending from theactuator shaft54 just below the O-ring seal60.
• In this manner, thespring88 urges theactuator shaft54 axially upward, and thus, thevalve42 into thealiquot chamber22. As such, absence any external force, fluid communication between thealiquot chamber22 and the collection chamber20 (shown inFIGS. 2 and 3) is prevented. However, when a user pushes axially downward on theboss56, and thus theactuator shaft54, against the urging force of thespring88, thevalve42 is displaced from thealiquot chamber22, thereby allowing fluid communication between thealiquot chamber22 and the collection chamber20 (FIG. 5). When the user releases theboss56, and thus theshaft54, the urging force of thespring88 will cause theactuator shaft54 to axially move upward, thereby moving thevalve42 back into thealiquot chamber22 to prevent fluid communication with the collection chamber20 (FIG. 6). In an alternative embodiment, theboss56 is eliminated, and the user need only push down or release the top of theactuator shaft54. The end of theactuator shaft54 may be recessed within thevial cap84, in which case, the user may push down on theactuator shaft54 using a simple tool.
• In the previously illustrated embodiments, the valve mechanisms selectively prevent fluid communication between thealiquot chamber22 andcollection chamber20 by placing the valve within thealiquot chamber22. In other embodiments, the valve mechanism may have a valve that directly interfaces with thealiquot chamber22 in other manners to prevent such fluid communication.
• For example, referring toFIGS. 7 and 8, another alternative embodiment of thevial cap94 will be described. Thevial cap94 is identical to thevial cap14 illustrated inFIGS. 2 and 3, with the exception that it comprises avalve mechanism96 that seals thealiquot chamber22 at the interface with thecollection chamber20. In particular, thevalve mechanism96 comprises avalve98 configured to be selectively displaced from alower-most edge100 of the innerannular flange28 to allow fluid communication between thealiquot chamber22 and the collection chamber20 (FIG. 7), and placed against thelower-most edge100 of innerannular flange28 to prevent fluid communication betweenaliquot chamber22 and collection chamber20 (FIG. 8).
• When preventing fluid communication between the respective chambers, thevalve98 sealingly bears against thelower-most edge100 of the innerannular flange28. To this end, thevalve98 includes anannular flange102 that has a diameter greater than the diameter of thealiquot chamber22 and an O-ring seal104 seated within anannular recess106 within the upper surface of theflange102, so that the O-ring seal104 can contact thelower-most edge100 of the innerannular flange28 in order to facilitate the sealing arrangement.
• In the same manner described above with respect toFIGS. 2 and 3, axial movement of theactuator shaft54 is accomplished by rotationally translating the boss56 (shown by arrow), and thus, theshaft54, to operably move thevalve98 relative to thealiquot chamber22. That is, clockwise rotation of theboss56 causes theshaft54, and thus thevalve98, to move axially downward, and counterclockwise rotation of theboss56 causes theshaft54, and thus thevalve98, to move axially upward. Alternatively, in the same manner described above with respect toFIGS. 5 and 6, the valve mechanism may be configured, such that theshaft54 need only be axially translated, i.e., without rotational translation.
• It should be appreciated that the incorporation of the aliquot chamber and valve assembly into the vial cap, as illustrated inFIGS. 1-8, allows thevial10 to be stored upright in a standard manner without hindrance by any portion of the valve mechanism protruding from the vial and without risk that the remaining portion of the sample contained in thecollection chamber20 will leak into thealiquot chamber22 with thevial10 is stored upright. In addition, incorporation of the aliquot chamber into the vial cap provides the option of separating the vial cap containing the aliquot sample from the vial body, transferring the separated vial cap with the contained sample aliquot to a different location for molecular testing, and recapping and leaving the vial body at the cytological laboratory for producing a slide specimen or for any other reason. However, in the case where the aliquot chamber is incorporated into the vial cap, thevial10 will need to be turned upside down to flow the sample aliquot from thecollection chamber20 into thealiquot chamber22. In the case where an automated specimen preparation process is to be used to transfer the aliquot sample into thealiquot chamber22, this would require an additional step of flipping the vial upside down. Also, because the aliquot sample will be subsequently tested, it is prudent that separate sample indicia (not shown) be placed on thevial cap14 in addition to thevial container12 to eliminate or minimize the possibility that vial caps and vial containers will be incorrectly mated together.
• As illustrated inFIGS. 9 and 10, an embodiment of asample vial110, wherein the aliquot chamber and valve mechanism are integrated into the vial container, will now be described. In this case, thevial110 need not be turned upside down to flow the sample aliquot from the collection chamber into the aliquot chamber, and because the aliquot chamber is not incorporated into the vial cap, separate sample indicia is not required for the vial cap. In particular, thevial110 comprises ahollow vial container112 and avial cap114 that can be placed onto thevial container112 to enclose a sample contained within thevial container112. Thevial container112 andvial cap114 are identical to thevial container12 andvial cap14 illustrated inFIGS. 1-3 in all respects, with the following exceptions.
• Because thevial cap114 does not carry an aliquot chamber and valve mechanism, thevial cap114 may be a standard vial with includes a singleannular flange126 for mating with the top of thevial container112. Like thevial110 illustrated inFIGS. 2 and 3, thevial110 comprises acollection chamber120 formed within thevial container112 for collection of the sample, analiquot chamber122 for containing the aliquot sample, and avalve mechanism124 for selectively sealing and unsealing thealiquot chamber122 from thecollection chamber120, so the aliquot sample can be transferred from thecollection chamber120 into thealiquot chamber122 where it can be isolated from the remaining portion of the sample within thecollection chamber120. However, unlike the vial illustrated inFIGS. 2 and 3, thealiquot chamber122 andvalve mechanism124 are carried by thevial container112.
• In particular, anannular flange128 is formed at the bottom of thevial container112 to define thealiquot chamber122, which absent thevalve mechanism124, would normally be in fluid communication with thecollection chamber120. Thevalve mechanism124 includes avalve142 that is configured to directly interface with thealiquot chamber122 to allow or prevent fluid communication with thecollection chamber120. In the embodiment illustrated inFIGS. 9 and 10, thevalve142 is configured to be selectively displaced from the aliquot chamber to allow fluid communication between thealiquot chamber122 and the collection chamber120 (FIG. 9), and located within thealiquot chamber122 to prevent fluid communication between thealiquot chamber122 and the collection chamber120 (FIG. 10).
• Thevalve142 interfaces with theannular flange128 in the same manner as thevalve42 interfaces with the innerannular flange28 of thevial cap14 illustrated inFIGS. 2 and 3. That is, as best shown inFIG. 11, when preventing fluid communication between the respective chambers, thevalve142 sealingly bears against theinner surface144 of theannular flange128. Thevalve142 includes anannular flange146 that has a diameter slightly smaller than the diameter of thealiquot chamber122 and an O-ring seal148 seated within anannular recess150 formed around the circumferential edge of theflange146, so that the total diameter of thevalve142 is slightly greater than the diameter of thealiquot chamber122 in order to facilitate the sealing arrangement.
• Notably, because theannular flange128 is set off from the outer wall of thevial container112, the risk of interfering with the sealing relationship between thevalve142 and theinner surface144 of theannular flange128 is minimized. That is, if an inner annular flange is not used, and instead, thevalve142 sealingly interfaces with the inner surface of the outer wall of the vial container, the act of simply grasping the vial container may warp the outer wall, thereby breaking the sealing relationship between thevalve142 and outer wall. Alternatively, if the outer wall of thevial container112 is sturdy enough, thevalve142 could be made to interface with the inner surface of the outer wall without risk of interfering with the sealing relationship.
• Thevalve mechanism124 further includes anactuator152, which includes ashaft154 coupled to thevalve142 and extending through alower bore158 formed at the bottom of thevial container112. Unlike theactuator52 illustrated inFIGS. 2 and 3, theactuator152 does not include a boss or any part that protrudes from the vial container, so that the bottom surface of thevial110 is flush or recessed to facilitate the storage of thevial110 in an upright manner. Instead, theshaft154 is configured, such that a tool can be used to externally manipulate thevalve mechanism124 to selectively locate thevalve142 within thealiquot chamber122 and displace thevalve142 from thealiquot chamber122, as will be described in further detail below. Theannular flange146 of thevalve142 and theshaft154 may be conveniently formed from the same material as a unibody design, e.g., in an injection molding process using a plastic material, such as polypropylene.
• As best shown inFIG. 11, in order to prevent fluid communication between thealiquot chamber122 and the external environment that may otherwise occur through thelower bore158, thevalve mechanism124 includes an O-ring seal160 seated within anannular recess162 formed around the circumference of theshaft154. The O-ring seal160 axially moves within an enlargedupper bore164 between thelower bore158 and thealiquot chamber122. In the illustrated embodiment, theupper bore164 is defined by an innerannular flange166 formed withinvial container112, so that the O-ring seal160 bears against aninner surface168 of the innerannular flange166. Thus, the O-ring seal160 axially moves within theupper bore164 in a sealing arrangement to allow theactuator shaft154, and thus, thevalve142, to move up or down relative to aliquotchamber122, while preventing fluid communication between thealiquot chamber122 and the external environment through thelower bore158.
• In the embodiment illustrated inFIGS. 9 and 10, axial movement of theactuator shaft154 is accomplished in the same manner as theactuator shaft54 described with respect toFIGS. 2 and 3. That is, theactuator shaft154 may be rotationally translated to operably move thevalve142 relative to thealiquot chamber122. To this end, a threadedarrangement170 is provided between theactuator shaft154 and theupper bore158. Thus, clockwise rotation of theshaft154 causes thevalve142 to move axially upward, and counterclockwise rotation of theshaft154 causes thevalve142 to move axially downward. A slot or other suitable pattern is formed at the end of theshaft154 to allow a tool, such as a screw driver, to be mated with theshaft154 for subsequent rotation thereof.
• Alternatively, in the same manner described above with respect toFIGS. 5 and 6, the valve mechanism may be configured, such that theshaft154 need only be axially translated, i.e., without rotational translation. Or, in the same manner described above with respect to FIGS7 and8, the valve mechanism may be configured, such that the valve seals thealiquot chamber122 at the interface with thecollection chamber120, e.g., creating a seal between the upper-most edge of the innerannular flange128 and a valve.
• To allow user access to the aliquot sample, thevial container112 includes anaccess port172 adjacent thealiquot chamber122 and a sealing mechanism in the form ofseptum174 seated within theaccess port172 to seal it, thereby preventing fluid communication from thealiquot chamber122 through theaccess port172 until the user is ready to remove the aliquot sample from thealiquot chamber122 for examination. User access to the aliquot sample can be accomplished, e.g., by puncturing theseptum174 with a syringe and drawing the aliquot sample from thealiquot chamber122 into the syringe. Alternatively, a seal may be bonded on top surface of thevial cap114 above theaccess port172 or a screw-on plug or cap can be used to seal theaccess port172.
• Having described the structure and function of several embodiments of vials, a method of processing a vial will now be described with reference toFIG. 12. The illustrated method will be described in the context of triaging patients for precursors of cervical cancer.
• First, the vial cap is removed from the vial container and a fluid-based cervical-vaginal sample is placed within the collection chamber of the vial container (step200). This step can typically be accomplished at the physician's office. In the illustrated method, the cervical-vaginal sample is taken as part of the routine Pap smear. In particular, cells are scraped from the cervix of the patient and mixed into a preservative solution, such as PreservCyt® transport medium, contained within the collection chamber of the vial container. Next, the vial cap is placed back on the vial container, and the vial with the collected fluid-based sample, is transferred to a cytological laboratory (step202).
• At the cytological laboratory, the fluid-based sample is agitated to disburse the cells (step204), and the aliquot chamber in the vial is unsealed from the collection chamber while the vial cap is mated with the vial container (step206). In the embodiments illustrated inFIGS. 2 and 3, this is accomplished by rotating theboss56 on thevial cap14 in the clockwise direction to displace thevalve42 out of thealiquot chamber22. In the embodiment illustrated inFIGS. 5 and 6, this is accomplished by pushing theboss56 on thevial cap84 downward against the urging force of thespring88 to displace thevalve42 out of thealiquot chamber22. In the embodiment illustrated inFIGS. 7 and 8, this is accomplished by rotating theboss56 on thevial cap94 in the clockwise direction to displace thevalve98 away from thelower-most edge100 of the innerannular flange28. In the embodiment illustrated inFIGS. 9 and 10, this is accomplished by rotating theshaft154 in the clockwise direction with the special tool to displace thevalve142 out of thealiquot chamber122.
• Next, an aliquot of the sample is flowed from the collection chamber into the unsealed aliquot chamber while the sample is isolated from an environment exterior to the vial (i.e., while the vial cap is mated with the vial container) (step208). In vials wherein the aliquot chamber is integrated into the vial cap, such as the embodiments illustrated inFIGS. 2 and 3,FIGS. 5 and 6,FIGS. 7 and 8, andFIGS. 9 and 10, this can be accomplished by flipping the vials upside down. In vials wherein the aliquot chamber is integrated into the vial container, such as the embodiment illustrated inFIGS. 9 and 10, the aliquot of the sample will flow from the collection chamber into the aliquot chamber in response to unsealing the aliquot chamber from the collection chamber instep204.
• Alternatively, if screw-type valve mechanisms are used, such as those illustrated inFIGS. 2 and 3,FIGS. 7 and 8, andFIGS. 9 and 10, the agitation, unsealing, and flowingsteps204,206,208 can be performed at the physician's office prior to transferring the respective vial to the cytological laboratory.
• Next, the aliquot chamber is sealed from the collection chamber to isolate the aliquot chamber from the remaining portion of the sample contained in the collection chamber (step210). In the embodiments illustrated inFIGS. 2 and 3, this is accomplished by rotating theboss56 on thevial cap14 in the counterclockwise direction to relocate thevalve42 into thealiquot chamber22. In the embodiment illustrated inFIGS. 5 and 6, this is accomplished simply be relieving downward pressure from theboss56 on thevial cap84, and allowing the urging force of thespring88 to move thevalve42 back into thealiquot chamber22. In the embodiment illustrated inFIGS. 7 and 8, this is accomplished by rotating theboss56 on thevial cap94 in the counterclockwise direction to abut thevalve98 against thelower-most edge100 of the innerannular flange28. In the embodiment illustrated inFIGS. 9 and 10, this is accomplished by rotating theshaft154 in the counterclockwise direction with the special tool to relocate thevalve142 into thealiquot chamber122.
• Next, the vial cap is unmated from the vial container to expose, and thereby provide access, to the remaining sample portion in the collection chamber (step212), and at least some of the remaining sample portion is transferred from the collection chamber to a microscope slide while the aliquot chamber is sealed from the collection chamber (step214). Typically, exposing the collection chamber to the external environment may expose the remaining sample portion to contaminants (e.g., HPV) at the molecular level. This may be especially true if the slide preparation process is performed by an automated specimen preparation system where molecular contaminants are often found. Without taking additional precautions, such molecular contaminants can be found in an aerosol or within filtered cell solution in the plumbing of the automated specimen preparation system where it can be transferred from vial to vial. However, because the aliquot sample in the aliquot chamber is isolated from the collection chamber, it will not be exposed to any contaminants that may enter the collection chamber.
• Next, the slide specimen is reserved for cytological screening of the sample for precursors of cervical cancers (step216), and the sample aliquot is reserved for DNA testing, e.g., for the present of high-risk HPV in the sample (step218). Next, the slide is cytological screened, e.g., for precursors of cervical cancers (step220). This can be accomplished in the same laboratory at which the slide was prepared, or alternatively, can be transferred to another laboratory. In the case where no abnormal cells are found, the patient is returned to a routine Pap smear schedule (step222). In the case of an ASC-US+ result, the patient is scheduled for a colposcopy/biopsy at the physician's office (step224). In the case of an ASC-US result, the aliquot sample is removed from the aliquot chamber via the access port within the vial cap or vial container (step226), and a reflex DNA test is performed on the aliquot sample reserved instep218 for the presence of high-risk HPV (step228). This can be accomplished using Digene's Hybrid Capture II HPV DNA assay. If the presence of high-risk HPV is detected in the sample, the patient is scheduled for a colposcopy/biopsy at the physician's office (step230), or alternatively may be placed on a schedule with increased Pap smear intervals. If the presence of high-risk HPV is not detected in the sample, the patient may then be returned to a routine Pap smear schedule (step232). Optionally, other DNA tests, e.g., to detect the presence of such asChlamydia trachomatisandNeisseria gonorrhoeae, may be performed. These other DNA tests, or even the HPV DNA test, can be alternatively performed in parallel with the cytological screening of the slide.
• In another aspect, disclosed herein is an instrument for automatically transferring an aliquot of a biological sample from the collection chamber of a vial to an aliquot chamber within the cap of the vial. The instrument comprises a mechanical arm for retrieving a vial, and an actuator for opening an aliquot chamber within the vial cap.
• In some embodiments, a vial is placed within the instrument. In certain embodiments, individual vials are placed within the instrument. In other embodiments, the vials are placed on or within a tray and the tray is placed within the instrument. By “within the instrument” it is meant that the vial is placed within the reach of the mechanical arm used for retrieving the vials. Thus, in some embodiments, the vial or the tray is placed in close proximity to the instrument, whereas in other embodiments, the mechanical arm is within an enclosed chamber and the vial or tray is placed inside the enclosed chamber. In some embodiments, the instrument further comprises a transport mechanism, upon which the vial or tray is placed and is then transported to an area of the instrument within the reach of the mechanical arm.
• In some embodiments, the mechanical arm grabs the vial by its cap, whereas in other embodiments, the mechanical arm grabs the vial by its body. In other embodiments, the mechanical arm lifts the vial from the bottom of the vial.
• In certain embodiments, the instrument further comprises an agitator. The agitator mixes the contents of the vial to break up blood, mucous and/or cell clusters and to disburse the cells within the sample. In some embodiments, the agitator rotates the vial at relatively high rotational speeds. In other embodiments, the agitator shakes the vial. In still other embodiments, the agitator is a sonicator that applies ultrasound energy to agitate the contents of the vial.
• In some embodiments, the mechanical arm picks up the vial and deposits it at the agitator. In certain embodiments, the mechanical arm continues to hold onto the vial while the contents of the vial are agitated. In other embodiments, the mechanical arm releases the vial at the agitator.
• In the embodiments that an agitator is used, following the agitation step thealiquot chamber22 is opened and filled with fluid. Various means for opening thealiquot chamber22 within the vial cap have been disclosed herein. In some embodiments, the instrument comprises an actuator that opens the aliquot chamber within the vial cap. In certain embodiments, the actuator rotates theboss56 in a counterclockwise direction to open thevalve42 to allow fluid communication between thealiquot chamber22 and thecollection chamber20. In other embodiments, the actuator presses on theboss56 to obtain the same result. In some embodiments, the actuator is a component of the mechanical arm. In other embodiments, the actuator is a separate component of the instrument and is not attached to the mechanical arm.
• In some embodiments, the mechanical arm tilts or inverts the vial so that fluid flows from thecollection chamber20 into thealiquot chamber22. In some embodiments, the vial is inverted prior to the actuator causing an internal fluid port, e.g., thevalve42, to open. In other embodiments, the vial is inverted subsequent to the actuator causing thevalve42 to open.
• Once thealiquot chamber22 is filled with fluid, the actuator causes thevalve42 to close, and thereby terminating fluid communication between thealiquot chamber22 and thecollection chamber20. In some embodiments, the actuator rotates theboss56 in a clockwise direction to close thevalve42. In other embodiments, theboss56 releases the pressure on theboss56 and thevalve42 closes because of the urging of thespring88. Once thevalve42 is closed, the vial is reinverted to its right-side-up position and is placed in an output tray for removal from the instrument.
• In some embodiments, thealiquot chamber22 is surrounded by opaque walls. In these embodiments, it is difficult to visually ascertain whether a certain vial has been through the instrument and its aliquot chamber is filled or not. Thus, in some embodiments, the instrument further comprises a marker. Once thealiquot chamber22 is filled, the marker marks the vial in a specified location. The marking on the vials allows a user to quickly determine whether the aliquot chamber of the particular vial has been filled.
• In some embodiments, the instrument disclosed herein comprises a plurality of mechanical arms. In some embodiments, a first mechanical arm retrieves a vial from the input tray and delivers it to the agitator. In the embodiments where no agitator is used, the fist mechanical arm delivers the vial to the actuator for opening thealiquot chamber22. In some embodiments, a second mechanical arm retrieves the vial from the agitator and delivers the vial to the actuator for opening thealiquot chamber22. In other embodiments, a third mechanical arm removes the vial from the actuator and delivers it to the output tray.
• In other embodiments, the instrument comprises a single mechanical arm. In some of these embodiments, the mechanical arm carries a first vial to the agitator. Once the contents of the first vial is mixed, the arm carries the first vial to the actuator. While the actuator performs the function of filling thealiquot chamber22 of the first vial, the mechanical arm grabs a second vial and carries it to the agitator. Then, while the contents of the second vial is being mixed, the arm carries the first vial to the output tray, then grabs the second vial and carries it to the actuator, and then grabs a third vial and carries it to the agitator. This process is repeated until all of the vials are processed.
• In other embodiments, the above function is carried out using two mechanical arms. In these embodiments, a first mechanical arm retrieves the vial from a storage location and delivers it to the agitator, and a second mechanical arm retrieves the vial from the agitator after the collection chamber contents have been mixed. In other embodiments, the second mechanical arm retrieves the vial from the actuator and delivers it to an output tray. In further embodiments, a third mechanical arm retrieves the vial from the actuator and deliver it to an output tray.
• In some embodiments, the output tray is the same as the input tray. In these embodiments, the vials are arranged on a tray and are then put within the instrument. The mechanical arm removes a vial from the try, and after the instrument is completed the task of filling thealiquot chamber22, the mechanical arm returns the vial to the same location from whence it was removed. In other embodiments, the input tray and the output tray are different. In still other embodiments, the instrument disclosed herein is coupled with an automated slide processor, such as ThinPrep® 2000 or Thinprep® 3000 slide preparation systems (Cytyc Corp., MA). In these embodiments, once thealiquot chamber22 is filled, the mechanical arm places the vial in a location where the vial can be used in the automated slide processor.
• As discussed above, the minimum amount of sample in thevial container12 required by the Food and Drug Administration (FDA) for automated transfer onto a microscope slide using Cytyc's ThinPrep® 2000 or Thinprep® 3000 slide preparation systems is 20 mL. Thus, in some embodiments, the instrument further comprises a re-fill mechanism. The re-fill mechanism comprises a storage tank for holding a liquid into which the biological sample is suspended. Examples of such liquid include, but are not limited to, water, saline, a buffer solution, such as phosphate buffer saline (PBS), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid solution, (HEPES), and the like, or a commercially available solution, such as PreservCyt® (Cytyc Corp., MA). In some embodiments, the re-fill mechanism re-fills the vial after thealiquot chamber22 has been filled with the same solution that was used to dissolve the biological sample, and for the same volume as that of thealiquot chamber22. In some embodiments, thevial container12 holds 20 mL, and thealiquot chamber22 holds 4 mL. When the aliquot chamber is filled, the volume of fluid in thevial container12 is reduced to 16 mL. In these embodiments, the re-fill mechanism adds another 4 mL to thevial container12.
• In these embodiments, thevial cap14 further comprises second access port, in addition to theaccess port72, which allows for access into thevial container12, and which access port can be sealed using a septum. In certain embodiments, the re-fill mechanism further comprises a syringe in fluid communication with the storage tank. After the aliquot chamber is filled, the syringe is inserted into thevial container12 through the second access port, a volume, such as 4 mL, of liquid is added to thevial container12, and the syringe is removed from the vial.
• In some embodiments, the syringe is disposable, i.e., each syringe is used only once to fill a vial. The use of disposable syringes minimizes the chance of cross-contamination between the vials. In these embodiments, a hose connects the storage tank to a head. The head is configured to removably attach the needle of a syringe. The needle of a syringe is attached to the head, and after the needle is inserted into thevial container12, a volume, e.g., 4 mL, of solution is delivered. The needle is removed from the vial, and thereafter, the needle is detached from the head, whereupon the head obtains another needle to deliver another volume of solution to the next vial.
• In some of these embodiments, the re-fill mechanism also comprises a volume measurer. The volume measurer can be a flow meter, which, knowing the diameter of the hose, or the syringe, can measure the volume of the delivered solution. In other embodiments, the volume measurer is a chamber of known volume. Prior to each re-fill, the chamber is filled with the solution from the storage tank, and during re-fill, all of the solution within the chamber is emptied into thevial container12. Once the re-fill is completed, the chamber is filled again from the storage tank.
• Although particular embodiments of the present invention have been shown and described, it should be understood that the above discussion is not intended to limit the present invention to these embodiments. It will be obvious to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present invention. Thus, the present invention is intended to cover alternatives, modifications, and equivalents that may fall within the spirit and scope of the present invention as defined by the claims.

Claims (21)

1. An instrument for obtaining an aliquot of a biological sample, comprising:

a first mechanical arm configured for retrieving and positioning a vial adjacent to an actuator, the vial having a collection chamber and cap,

the actuator configured for opening an internal fluid port to place the collection chamber in fluid communication with an aliquot chamber located within the vial cap.

2. The instrument ofclaim 1, further comprising an agitator configured for mixing the contents of the collection chamber.

3. The instrument ofclaim 2, wherein the agitator mixes the contents of the collection chamber by one or more of rotating the vial, shaking the vial, and applying ultrasound energy to the contents of the collection chamber.

4. The instrument ofclaim 2, wherein the first mechanical arm is further configured to retrieve the vial from a storage location and deliver it to the agitator.

5. The instrument ofclaim 2, further comprising a second mechanical arm configured to retrieve the vial from a storage location and deliver it to the agitator, wherein the first mechanical arm retrieves the vial from the agitator after the collection chamber contents have been mixed.

6. The instrument ofclaim 1, further comprising a second mechanical arm configured to retrieve the vial from the actuator and deliver it to an output tray.

7. The instrument ofclaim 5, further comprising a third mechanical arm configured to retrieve the vial from the actuator and deliver it to an output tray.

8. An instrument for obtaining an aliquot of a biological sample stored in a vial having a collection chamber and a cap, the instrument comprising:

a first mechanical arm configured for retrieving the vial from a first storage location;

an agitator that receives the vial from the first mechanical arm, the agitator configured for mixing the contents of the collection chamber;

a second mechanical arm configured to retrieve the vial from the agitator and position the vial adjacent an actuator, the actuator configured for opening and closing an internal fluid port within the vial to place the collection chamber in fluid communication with aliquot chamber located within the vial cap;

wherein the second mechanical arm is further configured to tilt or invert the vial such that, when the actuator opens the internal fluid port, a portion of a fluid within the collection chamber flows into the aliquot chamber.

9. The instrument ofclaim 8, wherein the agitator mixes the contents of the collection chamber by one or more of rotating the vial, shaking the vial, and applying ultrasound energy to the contents of the collection chamber.

10. A method for obtaining an aliquot of a biological sample mixed in a solution contained in a collection chamber of a vial, the vial having a cap, and the cap comprising a sealable aliquot chamber, the method comprising:

retrieving the vial from a first location using a mechanical arm;

mixing the contents of the solution using an agitator;

opening an internal fluid port using an actuator to thereby place the vial collection chamber in fluid communication with an aliquot chamber located within the vial cap;

tilting or inverting the vial to cause a portion of the solution to flow from the collection chamber to the aliquot chamber;

closing the internal fluid port;

subsequent to closing the internal fluid port, placing the vial in a second location using a same or different mechanical arm.

11. The method ofclaim 10, wherein the agitator the agitator mixes the contents of the collections chamber by one or more of rotating the vial, shaking the vial, and applying ultrasound energy to the contents of the collection chamber.

12. The method ofclaim 10, wherein the internal fluid port is opened and closed by rotating a boss on the vial cap relative to the cap.

13. The method ofclaim 10, wherein the internal fluid port is opened and closed by respectively pressing and releasing a boss on the vial cap.

14. The method ofclaim 10, wherein the vial is retrieved from the first location and placed in the second location using a same mechanical arm.

15. The method ofclaim 10, wherein the vial is retrieved from the first location by a first mechanical arm, and placed in the second location by a second mechanical arm.

16. The method ofclaim 10, wherein the vial is tilted or inverted prior to opening the internal fluid port.

17. The method ofclaim 10, further comprising transferring the vial from the agitator to the actuator using a same or different mechanical arm as was used to retrieve the vial from the first location.

18. An instrument for obtaining an aliquot of a biological sample, comprising:

automated means for retrieving and positioning a vial adjacent an actuator, the vial having a collection chamber and cap; and

automated means for opening an internal fluid port within the vial to thereby place the collection chamber in fluid communication with an aliquot chamber located within the vial cap.

19. The instrument ofclaim 18, further comprising means for mixing the contents of the collection chamber.

20. The instrument ofclaim 19, further comprising means for retrieving the vial from a storage location and delivering it to the agitator.

21. The instrument ofclaim 19, further comprising means for retrieving the vial from the actuator and delivering it to an output tray.

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